Strongly Enhanced Antitumor Activity of Trastuzumab and Pertuzumab Combination Treatment on HER2-Positive Human Xenograft Tumor Models
Strongly Enhanced Antitumor Activity of Trastuzumab and Pertuzumab Combination Treatment on HER2-Positive Human Xenograft Tumor Models
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DOI：
10.1158/0008-5472.can-08-4597
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发表时间：
2009-12-15
期刊：
影响因子：
11.2
通讯作者：
Hasmann, Max
中科院分区：
文献类型：
--
作者：
Scheuer, Werner;Friess, Thomas;Hasmann, Max
人表皮生长因子受体（HER）家族在细胞存活和增殖中起重要作用，并与肿瘤发生有关。HER 2的过度表达与侵袭性疾病和不良预后相关。曲妥珠单抗是一种靶向HER 2的人源化单克隆抗体，已证明对HER 2阳性早期和转移性乳腺癌女性的生存益处。帕妥珠单抗是另一种单克隆抗体，是一种HER 2二聚化抑制剂，与曲妥珠单抗相比，它与HER 2上不同的表位结合，并抑制HER 2与其他HER家族成员（如HER 3和HER 1）形成二聚体。我们在HER 2阳性乳腺癌和非小细胞肺癌异种移植物中研究了这些药物单独使用和联合使用的抗肿瘤活性。我们的数据表明，曲妥珠单抗和帕妥珠单抗的组合具有强烈增强的抗肿瘤作用，并在两种异种移植模型中诱导肿瘤消退，这是任何一种单一疗法都无法实现的。在曲妥珠单抗单药治疗期间肿瘤进展后也观察到联合治疗的疗效增强。近红外荧光成像实验证实帕妥珠单抗与肿瘤的结合不受曲妥珠单抗预处理的损害。此外，我们通过体外试验表明，曲妥珠单抗和帕妥珠单抗都能有效激活抗体依赖性细胞毒性。然而，我们的数据表明，强烈增强的抗肿瘤活性主要是由于曲妥珠单抗和帕妥珠单抗不同但互补的作用机制，即抑制HER 2二聚化和预防p95 HER 2形成。[Cancer Res 2009;69（24）：9330-6]
The human epidermal growth factor receptor (HER) family plays an important role in cell survival and proliferation, and is implicated in oncogenesis. Overexpression of HER2 is associated with aggressive disease and poor prognosis. Trastuzumab is a humanized monoclonal antibody targeting HER2 and has proven survival benefit for women with HER2-positive early and metastatic breast cancer. Pertuzumab, another monoclonal antibody, is a HER2 dimerization inhibitor that binds to a different epitope on HER2 than trastuzumab and inhibits HER2 dimer formation with other HER family members such as HER3 and HER1. We investigated the antitumor activity of these agents alone and in combination in HER2-positive breast and non-small cell lung cancer xenografts. Our data show that the combination of trastuzumab and pertuzumab has a strongly enhanced antitumor effect and induces tumor regression in both xenograft models, something that cannot be achieved by either monotherapy. The enhanced efficacy of the combination was also observed after tumor progression during trastuzumab monotherapy. Near-IR fluorescence imaging experiments confirm that pertuzumab binding to tumors is not impaired by trastuzumab pretreatment. Furthermore, we show by in vitro assay that both trastuzumab and pertuzumab potently activate antibody-dependent cellular cytotoxicity. However, our data suggest that the strongly enhanced antitumor activity is mainly due to the differing but complementary mechanisms of action of trastuzumab and pertuzumab, namely inhibition of HER2 dimerization and prevention of p95HER2 formation. [Cancer Res 2009;69(24):9330-6]